Substance Abuse in Adolescents

1. Substance Abuse in Adolescents Yedidia Bentur, MD Israel Poison Information Center Rambam Medical Center Faculty of Medicine, Technion, Haifa, Israel

2. “We live in a decadent age. Young people no longer respect their parents. They are rude and impatient. They frequent taverns and have no self-respect.” Inscription on Egyptian tomb circa 3000 B.C.

3. Anti Drug Authority, Israel 2001 • 12 – 18y,  one use/year • Substances  volatiles 7.4%  medications w/o indication 6.1% sedatives 4.8%, methylphenidate 2.9%  illegal drugs (w/o cannabis) 5.4% Ecstasy 2.7%  cannabis 5%, (USA 20% - 50%) marijuana 4%, hashish 3.3%

4. Poison Information Center Data Adolescents, 2003

5. Volatile Substance Inhalant Abuse (VSIA) • Recreational use of volatile substances • Since 19th century,  use since 1960s • Age: 14 - 22y (9 – 29y) • Inexpensive, available, legal, easy to conceal and handle,perceived erroneously as safe • Sudden death with negative autopsy findings

6. Classification of inhalants • Volatile solvents  adhesives (glue sniffing), thinners, lighters, correction fluid, dry cleaning, gasoline • Aerosols (propellants and solvents) spray paint, hair spray, deodorizers • Gases  freons (air conditioning), halothane, N2O (whipped cream, laughing gas) • Nitrites sexual stimulants: amyl nitrite, butyl nitrite, cyclohexyl nitrite

7. Inhalants

8. Exposure • Dose inhaled depends on: concentration in preparation  mode of inhalation (container, aerosol, cloth, plastic bag, etc.) duration  number of exposures • Levels x100-1000 occupational thresholds

9. Factors affecting clinical response • Dose • Genetic factors • Diet • Alcohol consumption • Smoking habits • Concomitant drugs • Physical activity

10. Glue sniffing - toluene • Absorption 50% • Tmax 15 – 30min • Distribution to adipose tissues • Metabolism: liver, extensive (80%) inhibited by ethanol P450 (CYP 1A1) and ALDH2 polymorphism oxidation to benzoic acid  conjugation with glycine  hippuric acid

11. Toluene (2) • Excretion < 20% by inhalation, unchanged urinary hippuric acid (filtration + secretion) • Elimination  biphasic; triphasic in workers terminal T½ 15-90h • Chronic abuse: induction of P450 hippuric acid,  exhaled unchanged

12. Mechanism of toxicity • Perivascular myelin loss,degeneration of white matter(cerebral cortex, cerebellum) • Hypoxemia (freons, plastic bag) • Aspiration • Hypoperfusion • Sensitization of myocard to catecholamines • Irritation (freons) • Frostbites (freons)

13. Clinical manifestations • Nausea, vomiting, bronchospasm • Confusion, psychomotor impairment, drunkenness, disinhibition, dizziness, headache, slurred speech, drowsiness, ataxia • Hallucinations, delusions, mydriasisHR, BP, respiration, coma, seizures • Death: anoxia, respiration, arrhythmias

14. Clinical manifestations (2) • Distal renal tubular acidosis (toluene) • Hemolysis (nitrites) • Hepatitis (halogenated hydrocarbons) • Head trauma (freons – air conditioning) • Burns (concomitant smoking)

15. Normal Inhalant abuse

16. Clinical manifestations (3) • Sequelae: neuropsychiatric, irreversible epilepsy, atrophy, polyneuropathy cognition, psychosis • Withdrawal  tolerance, psychological addictionresembles alcohol withdrawal • Fetal solvent syndrome (glue and gasoline)

17. Diagnosis • High index of suspicion – thorough history  unexplained neuropsychiatric / C-V manifestations • ECG monitoring • High anion gap metabolic acidosis (esp. toluene) • Urinary hippuric acid: used in occupational biomonitoring  interference: dietary benzoic acid(prunes, cranberries, plums, Chinese preserves, black tea) • Toluene blood and urine levels: not useful

18. Treatment • Removal • Supportive • Avoid catecholamines:  arrhythmias • Tachyarrhythmias: propranolol IV, esmolol IV • No specific antidote

19. Cannabissativa

20. Cannabis • Cannabis sativa • Known in Asia for > 5,000y • 61 cannabinoids:  9-tetrahydrocannabinol (THC): psychoactive8-THC, cannabidiol, cannabinol • Smoked (joint, 20mg THC), eaten (cookies) • “Gateway” drug • Medicinal – dronabinol (Ronabin, 2.5mg)

21. Common types of cannabis • Marijuana (grass): leaves, flowers, stem (1-5% THC) • Hashish: dried and compressed resin (10% THC) • Hashish oil (30-50% THC) • Charas: resin; ~20% THC (India) • Bhang: leaves (India) • Dagga: (South Africa) • Kef

22. Toxicokinetics • Bioavailability: oral 10-20%, lung 20-30% rapid • Onset 10-60min, Tmax 2-4h • Distribution to adipose tissues (brain) • Metabolism: hydroxylation 11-OH--THC (active) 11-nor-9 carboxy--THC (inactive) • T½ 20-30h, chronic user 5d (1-12d), duration 1-8h • Individual variability (experience, tolerance) Toxic dose:psychoactive 3-15mg, lethal 30mg/kg

24. Mechanism of toxicity • Cannabinoid receptors nervous system (CB1):  of transmitter release immune cells (CB2): modulate cytokine release testis (CB1), LH, prolaction • Endocannabinoids: anandamide, 2-arachidonyl-glycerol • Stimulant • Sedative • Hallucinogen • Catecholamine (dopamine) release (abuse) • Inhibition of sympathetic reflexes

25. Neurotoxicity of cannabis • Acute effects mood cognition behavior psychmotor • Chronic effects antimotivational psychosis dependence

26. Clinical manifestations • Euphoria,  sensory awareness, time – space distortion, palpitations, sedation •  reaction time, incoordination,  performance • Impaired memory, depersonalization, hallucinations, paranoid psychosis • Tachycardia, orthostatic hypotension, conjunctival injection, slurred speech, ataxia

27. Clinical manifestations (2) • Chronic users: manic, schizophreniform, confusional psychosis acute & chronic respiratory toxicity • Children (cookies): pallor, fine tremor, ataxia, hypotonia, coma, apnea, HR • Contaminants: pulmonary aspergillosis, paraquat • Withdrawal: after 180mg/d, 2-3wks; lasting 48h restlessness, insomnia, anxiety, tremor, hot flushes

29. Diagnosis • High index of suspicion – thorough history • HR, conjunctival injection, altered mood / cognition • Urine THC: after 1h  days (acute), weeks (chronic) no correlation to severity  false negatives: dilution, lemon juice, vinegar, bleach, salt, Visine false positives: NSAIDs passive smoking  positive results • R/0 other drugs of abuse

30. Treatment • Reassurance • Benzodiazepines • Sinus tachycardia: β blockers ( rarely needed) • Orthostatic hypotension: IV fluids • No specific antidote • Not life threatening

31. Ecstasy 3,4-methylenedioxymethamphetamine - MDMA (hallucinogenic amphetamine)

32. אקסטזי אקסטה כדור מיצובישי עגול  120mg X10-100 variability

33. Toxicokinetics • Absorption, oral: rapid • Onset of action: 30-60 min • Peak action: 90 min • Duration of action: 4-6 h (could be >8 h) • Metabolism: liver, P450 and N-demethylation, some metabolites active • Urine excretion: 65% unchanged, 35% - metabolites • Elimination kinetics: non-linear

34. Mechanism of action • Hallucinogenic and stimulant • Serotonin release followed by prolonged depletion (wks) • Permanent destruction of serotonergic nerve endingsin every experimental model • Stimulate NorE release with  dose stimulate - and -adrenergic receptors • SIADH

37. Pattern of use • Usually at rave parties • Hours of dancing • Heavy water intake • Up to 10 tab / night • Repeated use → reinforcement

38. Clinical manifestations • Toxic dose: variable • Can be delayed for hours • Unpredictable severity of effects • Severe poisoning and death - even after 1 tablet • Causes of death: cardiac arrhythmias, hyperthermia, hyponatremia

40. Clinical manifestations (2) • “Positive”: mood, euphoria, talkative, intimacy • “Negative”: HR, anxiety, anorexia, bruxism, mydriasis • Next day: myalgia, somnolence, depression, concentration • Repeated use: tolerance to the positive effects • Frequent use, dose:  negative effects

41. Clinical manifestations (3) • Nausea, vomiting • Chest pain, HR, BP, arrhythmias, MI (rare), ARDS •  temp., dehydration, rhabdomyolysis, ARF, DIC • Seizures, brain hemorrhage / infarct / edema •  Na, myoglobinuria, metabolic acidosis • Hepatitis • Serotonin syndrome

42. Clinical manifestations (4) • Emotional instability, insomnia • Confusion, depression, suicidal thoughts • Flashbacks, hallucinations • Impaired cognition • Psychosis (paranoid), panick attack

43. Diagnosis / Evaluation • High index of suspicion - thorough history • Unexplained neuropsychiatric / C-V manifestations • Na, K, blood gases, CPK, myoglobin • ECG & cardiac monitoring • R/O complications, other diagnosis • Urine assay: qualitative (usually), quantitative • Blood level: not clinically useful

44. Differential diagnosis • Toxicological causes of agitation and seizurescocaine, amphetamines, TCA, MAO - I, isoniazid • Non-toxic causes alcohol withdrawal intracranial hemorrhage manic behavior, psychosis, seizure disorder metabolic disorder (e.g. hyperthyroidism) cardiovascular abnormalities

45. Management • Do not delay treatment ! • Sedation: benzodiazepinescaution neuroleptics (e.g. haloperidol): seizures,  temp., arrhythmias, dystonia • Supportive oxygenation, ventilation – as needed hypertension: nitroprusside seizures: benzodiazepines hyperthermia: sedation, cooling, hydration, dantrolene hyponatremia: water restriction? saline (0.9%? , 3%?)

46. General warning signs • Changes in school behavior • Mood changes • Dropping out of usual activities • Changed physical appearance • New friends / loss of old friends • Missing items / money • Change in sleep patterns • Depression / anxiety

48. Cannabis